Affective disorder is common, seriously disabling mental illness. We assert, based on a preliminary study of 20 families, that vulnerability to this disease is determined at least in part by HLA-linked genes on chromosome 6 and that it probably has an immunological basis. We proposed to study 100 families, each containing two or more first degree relatives with affective disorder. Psychiatric diagnoses, using RDC criteria, will be based on data obtained from the Diagnostic Instrument Schedule of NIMH, administered by personnel experienced with this instrument and with psychiatric family studies. Hypotheses concerning the transmission of HLA haplotypes in various constellations of affected and well family members will be tested. Specifically, we predict that 1) pairs of affected siblings in sibships with only two affected will share HLA haplotypes more oftern than expected by chance and more often than in families with three or more affected, and 2) that non-random distribution of HLA haplotypes to well and affected parent. We propose to investigate the nature of the relationship between affective disorder and HLA genes by studying families from two environmentally and ethnically different populations. We will determine whether in probands there is an increased risk for affective disorder associated with certain HLA-DR alleles. We will relate different presentations of affective disorder and other psychiatric diagnoses to the transmission of HLA haplotypes. We will determine whether other genes, e.g., Gm immunoglobulin alleles, interact with HLA in determining susceptibility to illness. We will investigate the pattern of transmission of immune response (Ir) genes, using lymphoproliferative response to synthetic antigens, in relation to the occurrence of affective disorder in family members. This project will provide more precise information for use in genetic counseling and for the identification of high risk individuals. It should improve recognition of the spectra of psychiatric manifestation in relation to genetic etiology and aid in the development of more specific therapies.